A family of growth regulators (originally called cef10, connective tissue growth factor, fisp-12, cyr61, or, alternatively, beta IG-M1 and beta IG-M2), all belong to immediate-early genes expressed after induction by growth factors or certain oncogenes. Sequence analysis of this family revealed the presence of four distinct modules. Each module has homologues in other extracellular mosaic proteins such as Von Willebrand factor, slit, thrombospondins, fibrillar collagens, IGF-binding proteins and mucins. Classification and analysis of these modules suggests the location of binding regions and, by analogy to better characterised modules in other proteins, sheds some light onto the structure of this new family [(PUBMED:7687569)].

The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins [(PUBMED:8412987), (PUBMED:8145250), (PUBMED:1864378)]. Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands [(PUBMED:8412987)]. A number of human diseases arise from mutations in VWA domains. Secondary structure prediction from 75 aligned vWF sequences has revealed a largely alternating sequence of alpha-helices and beta-strands [(PUBMED:8145250)].

One of the functions of von Willebrand factor (vWF) is to serve as a carrier of clotting factor VIII (FVIII). The native conformation of the D' domain of vWF is not only required for factor VIII (FVIII) binding but also for normal multimerisation and optimal secretion. The interaction between blood clotting factor VIII and VWF is necessary for normal survival of blood clotting factor VIII in blood circulation. The VWFD domain is a highly structured region, in which the first conserved Cys has been found to form a disulphide bridge with the second conserved one [(PUBMED:10807780)].

A hallmark of gamete interactions at fertilization is relative or absolute species specificity. A pig sperm protein that binds to the extracellular matrix of the egg in a species-specific manner was recently identified and named zonadhesin (Hardy, D. M., and Garbers, D. L. (1995) J. Biol. Chem. 270, 26025-26028). We have now cloned a cDNA for mouse zonadhesin (16.4 kb), and it demonstrates a large species variation in the numbers and arrangements of domains. Expression of mouse zonadhesin mRNA is evident only within the testis, and the protein is found exclusively on the apical region of the sperm head. There are 20 partial D-domains, found as tandem repeats, inserted between two of the four full D-domains and an additional partial D-domain. These domains are homologous to the D-domains of von Willebrand factor and alpha-tectorin. A region at the N terminus of the mouse cDNA contains three tandem repeats homologous to MAM domains. These are domains comprised of about 160 amino acids that are present in transmembrane proteins such as the meprins and receptor protein-tyrosine phosphatases, where they appear to function in cell/cell interactions. Additionally, mouse zonadhesin contains a mucin-like domain and a domain homologous to epidermal growth factor (EGF). A putative single transmembrane segment separates a short carboxyl tail from the extracellular region. The existence of MAM, mucin, D-, and EGF domains suggest that mouse zonadhesin functions in multiple cell adhesion processes, where binding to the extracellular matrix of the egg is but one of the functions of this sperm-specific membrane protein.

Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical approximately 250 kDa subunits into disulfide-linked multimers that may be > 20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clinical symptoms and the response to therapy.

The modular architecture of a new family of growth regulators related to connective tissue growth factor.

FEBS Lett. 1993; 327: 125-30

Display abstract

Recently, several groups have characterized and sequenced members of a new family of growth regulators (originally called cef10, connective tissue growth factor, fisp-12, cyr61, or, alternatively, beta IG-M1 and beta IG-M2), all of which belong to immediate-early genes expressed after induction by growth factors or certain oncogenes. Sequence analysis of this family revealed the presence of four distinct modules. Each module has homologues in other extracellular mosaic proteins such as Von Willebrand factor, slit, thrombospondins, fibrillar collagens, IGF-binding proteins and mucins. Classification and analysis of these modules suggests the location of binding regions and, by analogy to better characterized modules in other proteins, sheds some light onto the structure of this new family.

Collagens are typical mosaic proteins containing a number of shuffled domains. These domains have been classified by sequence similarity in order to characterize their structural and functional relationships to other proteins. This analysis provides an overview of homologies of collagen domains. It also reveals two new relationships: (i) a module common to type V, IX, XI, and XII collagens was found to be homologous to the heparin binding domain of thrombospondin; (ii) the modular architecture of a human type VII collagen fragment was identified. Its N-terminal globular domain contains fibronectin type III repeats located adjacent to a Von Willebrand factor type A module. The proposed structural similarities point to analogous subfunctions of the respective domains in otherwise distinct proteins.

We present a new protein from X. laevis skin termed "frog integumentary mucin B.1" (FIM-B.1) with a general structure similar to FIM-A.1 (formerly "spasmolysin"). The central region consisting of tandem repeats of 11 amino acid residues is probably a target for extensive O-glycosylation, whereas the C-terminal cysteine-rich domain shows pronounced homology with the C1-C2 domains and the C-terminal end of von Willebrand factor. Furthermore, we describe homology with antistasin, an anticoagulant peptide from a leech. We also discuss some implications concerning the evolutionary origin of von Willebrand factor. In situ hybridization studies revealed the expression of FIM-B.1 exclusively in mucous glands of the skin. This is comparable with FIM-A.1 but is in contrast to all other physiologically active peptides, which are synthesized in granular glands.

The precursor protein of von Willebrand factor (pro-vWF) consist of four repeated domains, denoted D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2. The domains D1 and D2 constitute the amino-terminal pro-polypeptide and the remaining domains mature vWF, generated upon proteolytic processing. We have shown previously that the pro-polypeptide of pro-vWF is obligatory for assembly of pro-vWF dimers into multimers, a process vital for efficient adhesion of platelets to an injured vessel wall. Here, we have employed full length vWF cDNA to construct a series of deletion mutants, based on the homology between the various domains. Specifically, the domains D', D3 or both were deleted and the multimeric pattern of the mutant vWF proteins was analysed after transient expression in COS-1 cells. It is demonstrated that in addition to the pro-polypeptide, both the D' and the D3 domain are required for multimer assembly. Furthermore, by analysing a construct containing only the domains D' and D3 next to the pro-polypeptide it is shown that this is the only part of the vWF protein involved in multimer assembly. Since, the formation of pro-vWF dimers relies on the carboxy-terminal area of mature vWF, it is concluded that multimer assembly is a process independent of dimerization.

A human umbilical vein endothelial cell cDNA library in lambda gt11 was screened with two previously described cDNA inserts for human von Willebrand factor. Among 16 positive isolates, two that hybridized with a probe corresponding to the amino terminus of von Willebrand factor were sequenced. Together, these four cDNA inserts span 6.5 kilobases of the von Willebrand factor mRNA sequence, completely specifying the 2050 amino acids of the subunit of mature, secreted von Willebrand factor and 24 residues of a precursor peptide. Approximately 77% of the sequence is contained in five types of repeated domains. Domain A consists of 193-220 amino acids and is present in three tandem copies between residues 497 and 1111. Domain B contains 25-35 amino acids and is present in three copies between residues 1533 and 1636. Domain C consists of 116-119 amino acids and is duplicated between residues 1637 and 1899. In contrast to the essentially contiguous repetition of domains A-C, the two copies of domains D and E are each separated by 804 and 1383 amino acids, respectively. Domain D1 contains 289 amino acids between residues 79 and 367, while domain D2 consists of 270 amino acids between residues 1171 and 1440. Domain E1 consists of 46 amino acids between residues 25 and 70, and domain E2 consists of 46 amino acids between residues 1453 and 1498. The triplicated A domains are notably poor in Cys content, while the remaining domains are Cys-rich. The A domains appear to be homologous to a 225-residue segment of complement factor B.(ABSTRACT TRUNCATED AT 250 WORDS)

Full-length human von Willebrand factor (vWF) cDNA was assembled from partial, overlapping vWF cDNAs. This cDNA construct includes a coding sequence of 8439 nucleotides which encode a single-chain precursor of 2813 amino-acid residues, representing a putative signal peptide, a prosequence and mature vWF of 22, 741 and 2050 amino acids, respectively. This represents the longest coding sequence determined to date. In-vitro expression of full-length vWF cDNA revealed the synthesis of a polypeptide with a mol. wt corresponding with that of the unglycosylated precursor. The precursor is a highly repetitive protein which consists of two duplicated (B, C), a triplicated (A), a quadruplicated (D) and a partly duplicated domain (D'), in the following order: H-D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-C1-C2-OH. Both the prosequence, composed of two D domains (D1, D2), and mature vWF harbor an arg-gly-asp ('R-G-D') sequence which has been implicated in cell-attachment functions. It is argued that the pro-sequence is equivalent to von Willebrand Antigen II (vW AgII).

Disease (disease genes where sequence variants are found in this domain)

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with VWD domain which could be assigned to a KEGG orthologous group, and not all proteins containing VWD domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.